The lesions typically appear as circumscribed, rough, scaly patches on sun-exposed skin, ranging from flesh-colored to reddish-brown (Figure 1). Although most AKs are asymptomatic; some may exhibit signs and symptoms such as thickening, burning, tenderness, or itching.

Figure 2.

Hyperkeratotic AK.

Figure 3.

Pigmented AK.

Expected results of diagnostic studies

Diagnosis is usually made clinically; however, a biopsy may help to rule out a squamous cell carcinoma (SCC) or other more advanced lesions. Blood work is not indicated. Dermoscopy may be used to aid in making the diagnosis of AK. A "strawberry" pattern can be observed, with an erythematous background, a pink-red pseudonetwork, undulated vessels surrounding hair follicles, white-yellow scale, and hair follicles with yellow keratotic plugs, and a surrounding white halo.

Diagnosis confirmation

Skin biopsy - pathology reveals hyperkeratotic lesions that are confined to the epidermis. Basal layer keratinocytes are dysplastic with altered nuclei that may extend toward the granular layer (Figure 4). The hair follicles, glands, and ducts are generally not involved.

Figure 4.

Histopathology of AK. (H&E, X40)

Fluorescence - areas of abnormal skin appear with pink fluorescence under Wood's lamp after exposure to methyl ester of 5-aminolevulinic acid (ALA), a precursor to protoporphyrin.

These diagnostic techniques can aid in differentiating AKs from other diagnoses, including:

Invasive squamous cell carcinoma (SCC). Begins similarly to an AK, but can metastasize; generally appears as a larger red ulcer with a granular base and thick border.

SCC in situ (Bowen disease). Lesions are usually solitary and larger, in the same distribution as AKs, but can occur in covered areas such as mucous membranes; can ulcerate and bleed.

Psoriasis. Salmon-pink plaques resulting from a genetic susceptibility toward hyperproliferation and inflammation; often seen with distinct nail changes; patients may also have arthritic changes.

Who is at Risk for Developing this Disease?

AKs are most prevalent in fair-skinned individuals with a history of significant sun exposure. Individuals with light-colored skin are six times more likely to develop AKs than individuals with dark-colored skin. AKs are most prevalent (40-60%) in countries close to the equator (e.g., Australia), and less prevalent (11-26%) in countries in the Northern hemisphere (e.g., USA and England).

The prevalence of AKs increases with advancing age, affecting 90% of people over age 80. AKs are more common in men than women. This has been documented in the US (27% vs. 10%), England (15% vs. 6%), and Australia (55% vs. 37%).

AKs are more common in immunosuppressed patients and in patients with some genetic disorders (i.e., xeroderma pigmentosum, autosomal recessive inherited type 1 and type 2 albinism). Organ-transplanted patients have a 250-fold greater risk of developing aggressive AKs.

The overall reported prevalence of AKs ranges from 23-61%, and the reported annual incidence of AK ranges from 12.6%-43.4%. Due to these high rates of prevalence and incidence, destruction of AKs is the most commonly performed outpatient dermatologic procedure in the US.

UVB radiation induces thymidine dimers in keratinocyte DNA. Under normal conditions, these are excised by repair mechanisms initiated by the p53 gene during the G1 rest phase of the cell cycle. Chronic UVB exposure results in mutations of the p53 gene on chromosome 17p132, resulting in replication of damaged DNA in these keratinocytes.

Signaling proteins such as interferon-I-stimulated gene factor 3 (ISGF-3), which act as important activators of transcription, are suppressed, resulting in interferon-alpha activation interference, and subsequent suppression of keratinocyte proliferation.

Systemic Implications and Complications

Several studies have demonstrated an association between the presence of AKs and the development of SCCs. There is consensus that immunosuppressed individuals, people with a prior history of skin cancer, and people with AKs of the lips, nose, ear, or eyelid are at increased risk of developing SCC.

The lifetime risk of developing SCC of the skin is estimated to be 9-14% in men and 4-9% in women in the US. A meta-analysis of 45 studies concluded that the annual rate of progression of an AK to an SCC in an average-risk person is between 8-24 per 10,000. For high-risk individuals, the progression rate over 3 years is between 12-30%.

Approximately 2% of SCCs originating in AKs metastasize; 7% recur locally. It is estimated that 20-25% of AKs will regress over the course of a year.

Treatment Options

Medical options (topical)

Ingenol mebutate is an extract from sap of the plant Euphorbia peplus (milkweed) that has been used for many years as a folk treatment for skin cancers and warts. In January 2012 ingenol mebutate was approved by the FDA as an inducer of cell death for the treatment of AKs in the concentrations of 0.015% gel applied daily for 3 consecutive days to a contiguous area of 25 cm2 on the face and scalp; and 0.05% gel applied daily for 2 consecutive days to a contiguous area of 25 cm2 on the or trunk and extremities.

Four multicenter, randomized, parallel-group, double-blind, vehicle-controlled studies, evaluated ingenol mebutate gel or placebo in patients with patients with actinic keratoses. The percent of patients with 100% clearance of AKs (CR) in the treated areas in pooled data from the face/scalp studies was 42.2% with Ingenol mebutate 0.015% gel OD for 3 consecutive days, compared with 3.7% with treatment with the vehicle gel (P<0.001). The percent of patients with > 75% reduction from the number of baseline AKs (PR) in the treated areas was 63.9 and 7.4%, respectively (p< 0.001). The median reduction of the number of AKs from baseline was 83% and 0%, respectively. Local skin reactions (LSRs) peaked at day 4 and rapidly decreased by day 8. A follow up study showed that 87.2% of lesions that cleared completely at the end of the study remained clear after 12-months post treatment.

CR in pooled data from the trunk/extremities studies was 34.1% with ingenol mebutate 0.05% gel OD for 2 consecutive days and 4.7% with placebo (p< 0.001). PR was 49.1 and 6.9%, respectively (p< 0.001). The median reduction of the number of AKs from baseline was 75 and 0%, respectively. In a follow up study 85.1% of lesions that cleared completely at the end of the study remained clear after 12-months post treatment. No serious drug-related adverse events were reported and adherence to the brief treatment regimen exceeded 98% in these studies.

Imiquimod cream (5% or 3.75%)*

5-fluorouracil (5-FU) (5%, 1%, or 0.5%)*

3% Diclofenac in 2.5% hyaluronan gel*

Trichloroacetic acid (TCA) peel (medium depth)

Surgical options

Cryosurgery with liquid nitrogen

Curettage (with or without electrodessication)

Dermabrasion

Excision

Physical modalities

Photodynamic therapy (PDT) with topical 5-aminolevulinic acid*

Photodynamic therapy (PDT) with topical methyl aminolevulinate

Lasers

Radiation

Intense Pulsed Light (IPL)

Combination therapies

Cryosurgery with liquid nitrogen followed by imiquimod (5% or 3.75%)

Cryosurgery with liquid nitrogen followed by 3% Diclofenac in 2.5% hyaluronan gel

5-FU prior to Cryosurgery with liquid nitrogen

5-FU prior to PDT

*US Food and Drug Administration (FDA)-approved treatments for AKs.

Optimal Therapeutic Approach for this Disease

Treatment decisions are based on anatomic location, size, and extent of the lesion(s), changes in lesion growth pattern, previous treatment, medical stability of the patient, and patient preference among therapeutic options.

Medical options (topical)

Imiquimod cream (5% or 3.75%)

Imiquimod 5% cream is an immune response modifier indicated for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic AKs on the face or scalp in immunocompetent adults. The recommended dosage is once daily, 2-3 times per week for up to 16 weeks. The US FDA approved imiquimod 3.75% topical immune response modifier in March 2010 for the treatment of clinically typical, visible, or palpable AKs.

This new formulation offers a convenient daily, 6-week dosing cycle and is indicated for application over larger areas of skin (as compared with imiquimod 5%), including the full face and balding scalp in adults. Subjects treated with imiquimod 3.75% who were 100% clear of AKs at 8-weeks post-treatment revealed that 67% remained clear at 6 months, and 40.5% remained clear at 1 year follow-up. A consensus panel on the treatment of AKs in 2006 stated that imiquimod and 5-FU are the most effective field-directed therapies for AK (for multiple lesions or an entire area at risk).

A distinct advantage in using imiquimod lies in its ability to induce immune memory, thereby minimizing the recurrences of AKs, as well as treating subclinical lesions. Adverse events are generally local and include erythema (27%), scabbing or crusting (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%).

The use of imiquimod in patients with autoimmune disease (such as lupus or psoriasis), although not absolutely contraindicated, should be avoided or used with caution.

5-fluorouracil (5-FU) (5%, 1%, or 0.5%)

Topical treatments, such as the chemotherapeutic agent 5-fluorouracil (5-FU), are most commonly used for patients with multiple lesions. 5-FU inhibits thymidylate synthetase and causes cell death in actively proliferating cells. The most common formulation is a 5% cream, applied twice daily for 2-4 weeks to the entire affected region. A 1% formulation is available, indicated to be used twice daily for 2-6 weeks.

5-FU selectively targets the damaged skin, causing an inflammatory response with erythema, necrosis, and erosion. Numerous side effects are associated with 5-FU, including pain, irritation, tenderness, burning, ulceration, and inflammation. As a result, patient compliance is a significant concern with this treatment.

Pulse (interval) therapy has been introduced to aid patients in tolerating the treatment. Pearlman et al. found that efficacy was not reduced (98% clearance of lesions) when patients were allowed to apply 5-FU for 1-2 days per week for 6-7 weeks; at 9-months follow-up, 86% of patients remained clear. A 0.5% micronized cream is now available for patients; recommended use is once daily for 1 month. Among patients who tolerate the treatment, complete clearance is reported in >50% of patients, and an 80% overall reduction in the number of AKs. 5-FU is listed as Category X due to its potential to cause fetal harm; its use is contraindicated in pregnant and nursing mothers.

Patients with DPD (dihydropyrimidine dehydrogenase deficiency) should be cautious when taking 5-flurouracil, as this enzyme is required to breakdown the drug to avoid potentially toxic reactions. The FDA lists this as a warning on certain drugs and not others containing this compound based on their approval/submission date, but even if not listed, it should be noted. Although this deficiency is rare, patients can be tested for this deficiency by detecting elevated serum levels of uracil and/or thymine (substrates for DPD) if the physician is concerned.

Symptoms of DPD deficiency include microcephaly, seizures, and hypertonia; however, these can be absent. If any patient started on 5-FU shortly thereafter exhibits fever, stomatitis, mucositis, and/or diarrhea, the patient should be tested for DPD deficiency. If deficient, the physician should strongly consider discontinuing 5-FU in favor of an alternative treatment.

Diclofenac (3%) in hyaluronan gel (2.5%)

Diclofenac is a topical nonsteroidal anti-inflammatory drug (NSAID) that is typically less effective than the other topical treatment modalities; however, it is also associated with the fewest and most tolerable side effects, due to its anti-inflammatory properties. Diclofenac has a higher affinity for COX-2, which is overexpressed in AKs. Diclofenac also works to inhibit proinflammatory cytokines as well as prostaglandins.

The hyaluronic acid in the topical diclofenac gel formulation aids in decreasing the diffusion time through the skin, thereby allowing a greater exposure of the epidermis to the active ingredient. The dosing regimen is twice daily topical application for 60-90 days, explaining to the patient that full clinical results may not be apparent until 30 days after cessation of therapy.

A meta-analysis of three randomized trials (n=364) found that treatment with diclofenac gel resulted in complete resolution of AKs in approximately 40% of patients as compared with 12% with placebo. In post-transplant patients, diclofenac achieved complete clearance in 41% vs. 0% for placebo; 45% of these patients remained clear at 2 years follow-up. No SCCs developed in the treated areas; however, 15% of patients did develop invasive SCCs outside the treated area. Caution should be taken when prescribing diclofenac to patients with hypersensitivity to aspirin or other NSAIDs.

Trichloroacetic acid (TCA) peel (medium depth)

Medium-depth chemical peel with 30-50% TCA has been shown to be as effective as topical 5-FU, but better tolerated and preferred by patients. In a 1995 study by Lawrence et al, a medium-depth chemical peel (Jessner's solution and 35% TCA) was applied to one side of the face, while 5% 5-FU was applied to the other side in 15 patients. Both the chemical peel and 5-FU resulted in 75% reduction in AKs at 1-month follow-up, which persisted throughout 12-months of follow-up.

Methodological flaws included non-blinding study design, small study sample, and lack of information on selection criteria and patient compliance. Further, the results at 6 and 12 months of follow-up are confounded by intervening treatment of persistent AKs (35% TCA and cryosurgery at 6 months, shaving at 12 months).

Another study by Swetter et al. compared treatments with either 30% TCA peel, 5-FU 5% cream applied twice daily for 3 weeks, or carbon dioxide laser for the reduction of AKs. At 3-months posttreatment, reductions in AKs were 89% with TCA, 83% with 5-FU, and 92% with laser. The patients found treatment with TCA to be the most tolerable among the treatment modalities compared.

Surgical options

Cryosurgery with liquid nitrogen

Cryosurgery with liquid nitrogen, the most common treatment for AKs in the US, is most appropriate when discrete AKs are present. With this procedure, liquid nitrogen is applied directly to AK lesions as a method of destruction, although it is a nonselective treatment, as both atypical and typical keratinocytes are destroyed. The procedure generally does not require the use of a local anesthetic and involves only mild pain and minor side effects, such as temporary post-procedure erythema.

Patients with darker complexions may experience post-procedure pigment changes, so this issue should be discussed with these patients when assessing treatment options. Hyperkeratotic lesions may be more resistant to this treatment, and so may require debriding prior to cryotherapy. Proper technique is important, as one study revealed that a 5-second pulse is associated with a 39% cure rate, while a 20-second pulse is associated with an 83% cure rate.

Curettage (with or without electrodessication)

Curettage, which involves the use of a curette to scrape away the lesion, is another common method of treatment for AKs. In some instances, curettage may be used in combination with electrosurgery to stop bleeding or apply more damage to the affected area. The primary advantage to curettage is the ability to submit the specimen for histopathologic analysis, particularly in cases where invasive SCC is suspected. Disadvantages of curettage include the need for local anesthesia and the potential for scarring.

Dermabrasion

According to the American Academy of Dermatology, dermabrasion, chemical peels (using trichloroacetic acid), and laser resurfacing by carbon dioxide laser have also been effective in the treatment of extensive AKs. While not widely utilized for AKs due to other, more evidence-based treatment options, dermabrasion offers the advantage of covering large anatomic sites, rather than spot treatment. This is one option for procedural field therapy.

Excision

Full-thickness elliptical excision for AKs is rarely performed by dermatologists, but is regularly performed by plastic surgeons, general surgeons, and general practitioners. Curettage or shave excision is done to remove atypical cells. This technique may also be followed by electrodessication to further remove atypical cells and provide hemostasis. There is significant risk of scarring, bleeding, infection, and dyspigmentation. This modality is not recommended for the treatment of multiple AKs.

PDT uses the topical agent 5-aminolevulinic acid (ALA) followed by blue light exposure, or methyl aminolevulinate followed by red light exposure, to selectively photosensitize the atypical cells of the AK lesion. Approximately 14-18 hours (for 5-ALA) or 3 hours (for methyl aminolevulinate) following application of the sensitizer, the skin is exposed to the specific light source, and the cells of the AK lesion are destroyed. New studies have demonstrated that shorter incubation times for ALA-PDT (1-3 hours) are just as effective as the longer incubation times (79%-94% clearance rates).

Methyl aminolevulinate requires curettage prior to therapy, and is useful for lesional therapy, not field therapy. Common side effects of PDT include erythema, stinging/burning, edema, and scaling or crusting of the lesion. The primary disadvantage of PDT used to be the need for treatment over a 2-day period. Studies have found PDT to be as equally efficacious as 5-FU (5%). Patients randomized to apply 5-FU twice daily for 3 weeks experienced a mean lesional reduction of 70% compared to 73% for the PDT group after 6 months of follow-up.

Advantages of PDT include selective absorption and treatment of subclinical lesions. The fluorescence of the photosensitizer may be visualized using a Wood's light prior to initiating therapy. More optimal cosmetic results are reported by physicians and patients as compared with cryotherapy; however, PDT is associated with a higher cost than other commonly used methods of treating AKs.

Lasers

Carbon dioxide laser resurfacing is an effective treatment for AKs if the lesions are extensive. Insurance companies will usually reimburse the cost of this procedure if the patient has failed other topical treatment modalities, such as imiquimod or 5-FU. Erbium YAG lasers have also been used to target narrow treatment areas. Laser therapy is a beneficial treatment option for patients on anti-coagulant therapy.

Radiation

An older treatment modality for AKs not widely used today is radiation. A case report in 2000 described a large AK on the forehead of a 66-year-old gentleman that was refractive to conventional treatment; fractionated radiotherapy with a cumulative dose of 28 Gy resulted in complete remission at 14-months follow-up. At low doses, fractionated radiotherapy may be indicated in patients who have failed other, more conventional treatments.

Intense pulsed light (IPL)

IPL is a noninvasive technique used to treat dyspigmentation and vascular changes in the skin associated with prolonged sun exposure. The light emitted is filtered to remove any UV wavelengths, and is generally targeted to the upper layers of the skin. Studies have investigated the use of IPL with topical ALA for photodynamic therapy of AKs. Using a pulse duration of 20-30ms and a fluence of 12-16 J/cm2, IPL was performed in two passes 4 hours after the topical application of 20% ALA. Although 50% of lesions showed clinical improvement after one treatment, only 42% were confirmed clear by histology.

Combination therapies

Cryosurgery with liquid nitrogen followed by imiquimod (5% or 3.75%)

Imiquimod 5% has been used in combination with liquid nitrogen, and there is especially good data in posttransplant patients. Tan et al reported that imiquimod 5% used postcryotherapy resulted in fewer total and subclinical AKs than the vehicle. Jorizzo et al. demonstrated this effect for the imiquimod 3.75% concentration as well; when applied daily for two 2-week cycles post-cryotherapy, subjects treated with cryosurgery plus imiquimod 3.75% experienced 60% complete clearance compared to only 30% of subjects treated with cryotherapy plus placebo. Currently, a clinical trial investigating the safety and efficacy of imiquimod 3.75% postcryotherapy for the treatment of AKs on the dorsal hands and forearms is underway.

Cryosurgery with liquid nitrogen followed by 3% diclofenac in 2.5% hyaluronan gel

Using 3% diclofenac in 2.5% hyaluronan gel after cryosurgery with liquid nitrogen has been an effective strategy and has also been used in the treatment of post-transplant patients. Berlin et al conducted a phase 4 trial involving 714 subjects randomized to either cryosurgery alone, or cryosurgery followed by 90 days of 3% diclofenac in 2.5% hyaluronan gel. Cumulative clearance (of both old and new AKs) rates were significantly higher for the combination therapy group compared to cryosurgery alone (64% vs. 32%).

Ingenol mebutate sequential to cryosurgery

Recently, a study evaluated the efficacy and safety of field treatment of AKs on the face or scalp with ingenol mebutate 0.015% gel following cryosurgery. The mean percentage reduction in AKs was higher for ingenol mebutate at 11 weeks (82.7% vs. 75.6%) and 12 months (68.2% vs. 54.1%; P = .002).

5-FU used in combination with PDT has been shown to be beneficial. 15 patients with multiple facial AKs applied 5-FU (5%) for 5 consecutive nights prior to treatment with PDT-ALA on day 6. At 1-month follow-up, 90% of the lesions had resolved in 14/15 patients; clearance remained 90% at 1 year follow-up.

Patient Management

There is consensus that all AKs on the lip, ear, or eyelid, and those in immunocompromised patients should be removed. Although progression to SCC is rare, it is a concern, and most dermatologists will advocate treating AKs early before invasive or metastatic disease can become a concern. AKs are also treated because of patient reports that they are painful, pruritic, or cosmetically displeasing.

Patients should be educated on avoidance of sun exposure (especially between 10 AM-4 PM) and the use of protective clothing and sunblock. Patients in high-risk groups should perform self-examinations to detect changes in addition to having regular dermatologic examinations.

Unusual Clinical Scenarios to Consider in Patient Management

Patients who are immunocompromised (e.g., organ transplant recipients or undergoing chemotherapy) or have genetic instability (e.g., xeroderma pigmentosum) or melanin deficiencies (e.g., autosomal recessive inherited type 1 and type 2 albinism) should be carefully monitored for the progression of AKs to SCCs. These patients should be vigilant in sun avoidance and routine examinations.

Major criteria associated with the progression of AK to SCC are inflammation or induration, diameter more than 1 cm, rapid enlargement, bleeding, erythema, and ulceration. Minor criteria are pigmentation, palpability, pain, pruritus, and hyperkeratosis.

What is the Evidence?

(This meta-analysis examines the evidence of the natural history and progression of actinic keratoses to squamous cell carcinoma. Forty-five articles were selected for their relevance to high-risk patients and groups appropriate for surveillance. The annual progression rate of AKs to SCC was found to be 8-24 per 10,000 for the general Australian population, and 12-30% over 3 years for high-risk persons with multiple AKs. Local recurrence was found to be 7%, while 2% of SCCs originating as AKs metastasize.)

(Authors offer an excellent overview of treatment options for AKs, along with preventive strategies and identifying high-risk patients for early detection and treatment of progressing lesions. Newer agents are discussed, as well as an in-depth discussion of available nonsurgical therapies.)

(Ko discusses the premalignant nature of AKs and the progression rate to SCCs. The controversy over whether or not to treat, and how to treat, AKs is debated in depth. Ultimately, due to the additive risk of progression in patients with multiple AKs, evidence is heavy to treat most lesions.)

(Toxicity related to treatment with 5-FU may have certain genetic components, as identified by these researchers. Interestingly, a pronounced dihydropyrimidine dehydrogenase (DPYD) gene/sex interaction exists for males, increasing the risk of 5-FU–related toxicity in this subset.)

(This important study led to the FDA's approval of imiquimod 3.75% cream for the field treatment of multiple AKs on the face and balding scalp, offering patients greater therapeutic options in treating their skin disease.)

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